PAIRS: Validating telomerase reverse transcriptase (TERT) as an intrinsic vulnerability toward sensitizing cancer to radiation

配对：验证端粒酶逆转录酶 (TERT) 作为癌症对辐射敏感的内在脆弱性

• 批准号: 10718390
• 负责人: Stephen J. Kron
• 金额: $ 47.24万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718390
• 关键词: Abscopal effect; Acceleration; Active Sites; Address; Adverse effects; Affect; Affinity; Aneuploidy; Antibiotics; Apoptosis; Biological Assay; Cancer Patient; Caring; Cell Aging; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cell division; Cells; Characteristics; Chemicals; Clinic; Clinical; Combined Modality Therapy; Cysteine; Cytotoxic T-Lymphocytes; DNA; DNA Damage; Data; Dendritic Cells; Dendritic cell activation; Distant; Dose; Double Strand Break Repair; Drug Modelings; Drug Targeting; Enzymes; Excision; Experimental Neoplasms; Failure; Gene Expression; Genotoxic Stress; Growth; Hand; Immune Evasion; Immunologic Cytotoxicity; In Vitro; Inbred BALB C Mice; Infiltration; Inflammation; Inflammatory Infiltrate; Ionizing radiation; Malignant Neoplasms; Measures; Mediating; Modeling; Modernization; Modification; Molecular Target; Mus; Natural Products; Neoplasm Metastasis; Nonhomologous DNA End Joining; Normal Cell; Normal tissue morphology; Outcome; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Property; Publishing; RNA-Directed DNA Polymerase; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Reaction; Recurrence; Resistance; Reverse Transcriptase Inhibitors; Role; Safety; Series; Signal Transduction; Solid Neoplasm; Structure; Supporting Cell; T-Cell Proliferation; TERT gene; Telomerase; Telomerase Inhibitor; Telomerase inhibition; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Translating; Treatment Efficacy; Tumor Immunity; Validation; Work; analog; anti-tumor immune response; cancer cell; cell immortalization; cell injury; clinically significant; drug development; homologous recombination; image guided; immune checkpoint blockade; immunogenic; immunogenicity; improved; in silico; in vivo; inhibitor; irradiation; lead optimization; natural product inspired; neoplastic cell; novel; oxidative damage; pre-clinical; programmed cell death ligand 1; radiation resistance; radiation response; repaired; response; senescence; success; targeted agent; telomere; tumor; tumor progression

Summary A favorable target for radiation synthetic combinations would be a feature of cancer cells critically involved in growth, signaling, repair, or survival that can be blocked with an otherwise non-toxic drug, leaving tumors vulnerable to radiation without adverse effects on normal tissue. This project is directed at validating inhibition of telomerase reverse transcriptase (TERT) as a means to enhance the therapeutic index of radiation and achieving key progress toward translating this strategy to the clinic. While TERT is not expressed in most normal cells, approximately 90% of cancers display reactivation of TERT expression, supporting the catalytic activity of telomerase to maintain telomere integrity despite deregulated growth. While drugs targeting TERT have displayed sufficient safety in patients to evaluate effects of blocking telomere repeat synthesis, this has failed in solid tumors, as telomere erosion is too slow to affect tumor progression. Beyond its essential role in cancer cell immortality, TERT also contributes to pathways that support multiple cancer hallmarks. By limiting oxidative stress, accelerating double strand break repair and supporting cell survival, TERT expression in cancer cells may confer clinically significant resistance to radiation. This raises the question whether transiently targeting TERT during radiotherapy to enhance the toxicity of the resulting DNA damage to the cancer cells might significantly improve the therapeutic index of radiation. In recently published work, our groups described a novel class of TERT inhibitors inspired by the antibiotic chrolactomycin. Like the natural product, our streamlined natural product analogs react with an active site cysteine in the TERT reverse transcriptase active site. The optimized inhibitor, NU-1, is otherwise nontoxic in vitro or in vivo, but inhibits telomerase activity at low micromolar concentrations. NU-1 confers sensitivity to radiation to TERT-expressing cancer cells. Our data suggest that TERT may promote non-homologous end- joining repair, thereby affecting repair pathway choice. Finally, using a syngeneic tumor model in BALB/c mice, we have demonstrated marked sensitization to radiation in vivo, apparently mediated by persistent DNA damage and increased anti-tumor immune response. With these preliminary studies in hand, we propose to 1) Dissect the roles of TERT in double strand break repair and immune evasion, and 2) Improve the drug-like properties of NU-1 and use these novel compounds to understand how best to obtain radiation sensitization and an effective anti-tumor immune response.

概括 辐射合成组合的一个有利的靶标将是癌细胞的特征 参与生长，信号传导，修复或生存，可以用原本无毒的药物阻塞，离开 肿瘤容易受到辐射的影响，对正常组织没有不利影响。该项目旨在验证 抑制端粒酶逆转录酶（TERT）作为增强辐射指数的一种手段 并取得了将该策略转化为诊所的关键进展。虽然大多数人都没有表达Tert 正常细胞，大约90％的癌症显示出TERT表达的重生，支持催化 端粒酶的活性以维持端粒完整性，尽管导致了增长。而靶向tert的药物 已经在患者中表现出足够的安全性，以评估阻断端粒重复合成的影响，这有 由于端粒侵蚀太慢而无法影响肿瘤进展，因此在实体瘤中失败。超越其在 癌细胞的不朽，TERT还有助于支持多个癌症标志的途径。通过限制 氧化应激，加速双链断裂修复和支撑细胞存活，TERT表达 癌细胞可能赋予临床上对辐射的显着抗性。这就提出了一个问题 靶向放射治疗期间的TERT以增强所得DNA损伤对癌细胞的毒性 可能会显着改善辐射的治疗指数。 在最近发表的工作中，我们的小组描述了一种新型的TERT抑制剂，灵感来自 抗生素性乳霉素。像天然产品一样，我们精简的天然产品类似物与活动 TERT逆转录酶活性位点中的位点半胱氨酸。优化的抑制剂NU-1是无毒的 体外或体内，但在低微摩尔浓度下抑制端粒酶活性。 NU-1赋予对 表达TERT癌细胞的辐射。我们的数据表明，TERT可能会促进非同源末端 连接维修，从而影响修复途径的选择。最后，使用BALB/C小鼠中的同基因肿瘤模型， 我们已经证明了对体内辐射的明显敏化，显然是由持续的DNA介导的 损伤和抗肿瘤免疫反应增加。通过这些初步研究，我们建议1） 剖析TERT在双链断裂修复和免疫逃避中的作用，2）改善药物样 NU-1的特性并使用这些新型化合物来了解如何最好地获得辐射敏化 和有效的抗肿瘤免疫反应。